Prostaglandins of the d series, and tranquilizers and soporifics containing the same

ABSTRACT

The present invention provides novel prostaglandins D, that is, 13,14-dihydro-15-keto-PGDs, which have an excellent sedative and sleep-inducing activity, and so they are useful for tranquilizer and/or soporifics.

This application is a divisional application of Ser. No. 07/403,774filed Sept. 6, 1989, U.S. Pat. No. 5,073,569, in turn acontinuation-in-part application of Ser. No. 07/149,272 filed Jan. 28,1988, the latter abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandins of D series(referred to as prostaglandins D or PGDs hereafter), and tranquilizersand soporifics containing the compound.

Prostaglandin is a general name for prostanoic acids which is divided inE, F, A, B, C, D, H and the like according to the way keto or hydroxylgroup introduced in five membered ring portions. In addition tostimulating uterine muscle, prostaglandins have various physiologicaland pharmacological activities such as vasodilation, inhibition ofblood-platelet aggregation, anti-inflammatory effect and the like.

Prostaglandin D contains the following five membered ring: ##STR1##classifying roughly, PGD₂ wherein C₅ -C₆ bond is double bond: ##STR2##and PGD₃ wherein C₁₇ -C₁₈ bond is double bond; ##STR3## are known. Forexample, PGD₂ is known to have activities such as analgesic activity,sedative activity, induction of sleep, thermoregulation and the like.However, activity which PGD₂ may show greatly depends on theadministration route thereof. For example, experiments using rats showthat physiological sleep can not be induced by peripheral administrationsuch as subcutaneous injection, intravenous injection, oraladministration and the like but induced by administrating directly inthe cerebral ventricle. Therefore, PGD₂ is difficult to administrate. Inaddition, PGD₂ also exhibits inhibition of blood-platelet aggregation,bronchoconstriction, constriction of enteron muscle, vasodilation andthe like as well as side-effect such as severe diarrhea. Therefore,there exist problems to use PGD₂ as tranquilizers and soporifics.

On the other hand, in metabolites of human or animal, the existence ofanalogues of prostaglandins D in the free form wherein carbons at 13 and14 positions are saturated and that at 15 position forms carbonyl groupis confirmed. These 13,14-dihydro-15-keto-prostaglandins D are ##STR4##and the corresponding PGD₁ and PGD₂ and, PGD₃ are known as metaboliteswhich are naturally produced in vivo by enzymatic metabolism. These13,14-dihydro-15-keto-PGDs have been reported as physiologically andpharmacologically inert metabolites which barely exhibit variousphysiological activities that PGDs usually do (Accta PhysiologicaScandinavica, 66, 509-(1966)).

SUMMARY OF THE INVENTION

In the course of study on the pharmacological activities of the abovemetabolites, 13,14-dihydro-15-keto-PGD₂, the present inventor has foundthat 13,14-dihydro-15-keto-PGD₂ exhibits sedative and sleep inductioneffect by intra-postcisternal and intracerebroventricularadministration, respectively. Further, while estimating pharmacologicalactivities of 13,14-dihydro-15-keto-PGDs derivatives, I have found that13,14-dihydro-15-keto-PGD analogues exhibit sedative and sleep inductioneffect, which is one of the pharmacological activities of -PGDs, byperipheral administration such as subcutaneous injection, intravenousinjection, oral administration as well as intraventricularadministration, when they are converted into the corresponding compoundswherein carboxylic acid is esterified, or salts thereof and those in thefree form or having a protective group, which contain substitutents at16, 17, 19 and/or 20 position, those with methyl or hydroxymethyl groupat 9 position, those with alkoxy group at the end of ω-chain and thosewith triple bond at the end of ω-chain and those with triple bond atcarbons at 5 and 6 positions. Moreover, I have found that13,14-dihydro-15-keto-PGD analogues never or barely exhibitpharmacological and physiological activities such as inhibition ofblood-platelet aggregation, bronchoconstriction, constriction ofenteron, vasodilation and the like, which PGDs usually have, and theyare not accompanied with side effect.

BRIEF DESCRIPTION OF THE INVENTION

FIG. 1-FIG. 22 show the n.m.r. spectrum of 13,14-dihydro-15-keto-PGDsderivatives of the present invention.

FIG. 23 shows a sleep inducing action of 13,14-dihydro-15-keto-PGD₂.

FIG. 24-FIG. 27 show results of sleep-elapse change after administrationof 13,14-dihydro-15-keto-PGDs.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides prostaglandins D represented by thegeneral formula: ##STR5## wherein (X) is ##STR6## R₁ is hydrogen,physiologically acceptable salt thereof, physiologically acceptableprotective group or C₁₋₄ alkyl;

R₂ is hydrogen or methyl;

R₃ is hydroxyl, methyl or hydroxymethyl;

R₄ and R₅ are same or different to represent hydrogen, methyl, hydroxylor halogen;

R₆ is C₁₋₉ alkyl which may be branched or contain double bond, or C₁₋₉alkyl which contains ether substituent wherein carbons at 2 and 3position may be doubly bonded; except when R₁, R₂, R₄ and R₅ arehydrogens, R₃ is hydroxyl, R₆ is n-butyl, carbons at 2 and 3 positionsare singly bonded, and (X) is A, C or D;

and tranquilizers and soporifics containing 13,14-dihydro-15-keto-PGDsas aforementioned.

(X) is the general formula (I) represents above four constructions.

The compound wherein --(X)-- represents ##STR7## is prostaglandins D₁,and the compound wherein --(X)-- represents ##STR8## is prostaglandinsD₂. Therefore, a compound wherein --(X)-- represents ##STR9## is6-keto-PGD₁ s, and ##STR10## is 5,6-dehydro-PGD₂ s.

In the present invention, R₁ represents hydrogen, ester residue, salt orprotective group. The preferred R₁ in the present invention is esterresidue. More preferably, it is saturated or unsaturated alkyl which maycontain side chain, especially alkyl which may contain C₁₋₄ side chain,for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl andthe like.

Free PGDs may form salt thereof with suitable alkali. When used as amedicament, physiologically acceptable alkali may be used. Such alkaliincludes alkali metal, alkaline earth metal, ammonia, lower amine,alkanolamine, heterocyclic compound, for example, sodium, potassium,calcium, magnesium, methylamine, dimethylamine, cyclopentylamine,benzylamine, piperidine, monoethanolamine, diethanolamine,monomethylethanolamine, tromethamine, lysine, tetraalkylammonium saltand the like.

As a protective group there are exeplified alkylsilicon such astrimethylsilicon, triethylsilicon and the like; tetrahydroxypyran andthe like.

R₂ is hydrogen or methyl and carbons at 2 and 3 positions may be doublybonded.

R₃ is hydroxyl, methyl or hydroxymethyl, wherein configuration of thecarbon at 9 position is α, β, or mixture thereof. Particularly, thosewith α-configuration is preferred.

R₄ and R₅ are independently represent hydrogen, methyl, hydroxyl orhalogen. R₄ and R₅ may be same or different.

R₆ is saturated or unsaturated C₁₋₉ alkyl which may be branched. C₄₋₉alkyl is preferred. As C₄₋₉ alkyl, straight alkyl or that having methylside chain is particularly preferable.

R₆ is saturated or unsaturated C₁₋₉ alkyl having ether substituent. Asalkyl group, C₂₋₆ alkyl, especially straight alkyl is preferred. Ethersubstituent includes methoxy and ethoxy. Particularly, those havingsubstituent at the end of their alkyl chains are preferred.

Typical examples of the compounds of the present invention will be shownbelow:

13,14-dihydro-15-keto-PGD₂ alkyl ester;

13,14-dihydro-15-keto-16,16-dimethyl-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-19-methyl-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-16R,S-fluoro-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-20-methoxy-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-18-methoxy-19,20-bisnor-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-19-ethoxy-20-nor-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-20-methoxyethyl-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-20-methoxy-Δ² -PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-16R,S-methyl-20-methoxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-19-methyl-20-methoxy-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-16R,S-fluoro-20-methoxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-5,6-dehydro-PGD₂ and alkyl ester thereof;

13,14-dihydro-15-keto-5,6-dehydro-20-methoxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-5,6-dehydro-β-hydroxy-PGD₂ and alkyl esterthereof;

13,14-dihydro-15-keto-5,6-dehydro-β-hydroxy-20-methoxy-PGD₂ and alkylester thereof;

and the like.

In order to synthesize the prostaglandins of the D series of the presentinvention, for example, as shown in the attached synthetic charts 1-8,commercially available corey lactone (1) is used as a starting material,which is subjected to collins oxidization to give aldehyde (2), and theresultant is reacted with dimethyl(2-oxoalkyl)-phosphonate to giveα,β-unsaturated ketone (3). The resulting α,β-unsaturated ketone (3) issubjected to chemical or catalytic reduction, followed by conversioninto ketanol, introduction of α-chain, Jones oxidization and the like togive the objective compound.

The prostaglandins of the D series of the present invention may be usedas a medicament for animals or human. Usually, they can be generally orlocally administered, for example, by oral administration, intravenousinjection, subcutaneous injection or the like. The dose level may varydepending on the animals, human, age, weight, conditions, therapeuticeffect, route of administration, period for treatment and the like.

Solid compositions for oral administration according to the presentinvention include tablets, powder, glanules and the like. In such solidcompositions, one or more active substances may be mixed with at leastone inert diluent, for example, lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. According tothe conventional manner, the composition may contain additives otherthan inert diluent, for example, lubricant such as magnesium stearate,disintegrants such as fibrous calcium gluconate, stabilizing agents suchas etherified cyclodextrin, e.g., α-, β- or γ-cyclo-dextrin, dimethyl-α,dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branchedcyclodextrin such as glucosyl-, maltosyl-cyclodextrin,formyl-cyclodextrin, cyclodextrin containing sulfur, misoprotol,phospholipid and the like. When the above cyclodextrins are used,clathrate compound may be formed to increase stability. Alternatively,liposome is formed using phospholipids to increase stability. Tablets orpills may be optionally coated with gastric or enteric film such assucrose, gelatin, hydroxypropylmethyl cellulose phthalate and the like.Alternatively, they may be coated with more than two layers. Further,they may be formulated as capsules using substances which can beabsorbed, such as gelatin.

Liquid compositions for oral administration may contain pharmaceuticallyacceptable emulsion, solution, suspension, syrup, elixir, as well asgenerally used inert diluent such as purified water, ethanol, vegetableoil, e.g., coconut oil. Such compositions may contain adjuvant such ashumectant, suspension, sweetener, flavor, preservatives in addition toinert diluent. Alternatively, such liquid compositions may be enclosedin soft capsules.

Other compositions for oral administration include sprays containing oneor more active substances, which can be formulated by known methods.

Injection for parenteral administration according to the presentinvention includes sterile, aqueous or non-aqueous solution, suspension,emulsion, or surface active agents.

Aqueous solution and suspension include, for example, injectabledistilled water and physiological saline. Non-aqueous solution andsuspension include, for example, propylene glycol, polyethylene glycol,vegetable oil such as olive oil, alcohols such as ethanol, Polysorbateand the like. Such compositions may further contain adjuvants such aspreservatives, humectants, emulsifying agent, dispersant and the like.They may be sterilized, for example, by filtration throughbacteria-retaining filter, or by compounding bactericide or byirradiation. Alternatively, sterile solid composition is prepared, whichis dissolved in sterile water or sterile solvent for injection beforeuse.

EXAMPLE 1 (CF. SYNTHETIC CHART 1) Synthesis of 13,14-dihydro-15-ketoPGD₂ ethyl ester (1), R=Et (1-1) Synthesis of1S-2-oxa-3-oxo-6R-(3-oxo-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane (3)

(-)-Corey lactone (1) (2.000 g) dissolved in dichloromethane (20 ml) wasoxidized using collins reagent to give aldehyde (2). sodium hydride(50%, 0.264 g) was suspended in dry THF (45 ml), and after adding asolution of dimethyl (2-oxo-heptyl)phosphonate (1.475 g) in THF, stirredat room temperature for 90 minutes. A solution of aldehyde (2) in THF(40 ml) was added dropwise to the above solution and let to standovernight at room temperature. The crude product obtained after theusual work-up was chromatographed (ethyl acetate/hexane (1:3)). Yield,1.618 g (64%).

(1-2) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(5)

Saturated ketone (4) obtained after catalytic hydrogenation of enone (3)(1.618 g) with palladium on carbon and hydrogen was converted into thecorresponding ketal (5) using ethylene glycol and p-toluenesulfonic acidin benzene. Yield, 0.2010 g (70%).

(1-3) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-octyl)-7R-hydroxy-bicyclo(3,3,0)-octane(6)

Potassium carbonate (0.116 g) was added to ketal (5) (0.2010 g) inabsolute methanol, and stirred at room temperature. After the reactionwas completed, acetic acid was added. The crude product obtained afterthe usual work-up was chromatographed (ethyl acetate/hexane (1:1)) togive alcohol (6). Yield, 0.090 g (73%).

(1-4) Synthesis of 13,14-dihydro-15,15-ethylenedioxy-PGF₂ α(8)

Alcohol (6) (0.090 g) was reduced in toluene withdiisobutylalumiumhydride (DIBAL-H 1.5-M) to give lactol (7). Accordingto the conventional method, a solution of lactol (7) in DMSO was addedto ylide obtained from (4-carboxy-butyl)triphenylphosphonium bromide(0.5406 g) in DMSO to give 13,14-dihydro-15,15-ethylenedioxy-PGF₂ α(8).Yield, 0.0644 g (53%).

(1-5) Synthesis of 13,14-dihydro-15,15-ethylenedioxy-PGF₂ αethyl ester(9), R=Et

Carboxylic acid (8) (0.0644 g) was esterified with diazobicycloundecene(DBU) (0.024 ml) and ethyl iodide in acetonitrile (10 ml) at 60° C. toyield ethyl ester (9). Yield, 0.0594 g (86%).

(1-6) Synthesis of 13,14-dihydro-15-keto-PGF₂ αethyl ester (10), R=Et

Ethyl ester (9) was dissolved in a mixed solvent (acetic acid/water/THF(3:1:1)) (6 ml) and kept at room temperature. The crude product obtainedafter the usual work-up was chromatographed (ethyl acetate/hexane (1:1))to give 13,14-dihydro-15-keto-PGF₂ α ethyl ester (10). Yield, 0.0457 g(86%).

(1-7) Synthesis of 13,14-dihydro-15-keto-PGD₂ ethyl ester (11), R=Et

Ethyl ester (10) (0.0457 g) was oxidized with Jones reagent in acetone(10 ml). After the usual work-up, the resulting crude product waschromatographed (ethyl acetate/hexane (1:3)). Yield, 0.0260 g (57%)).

Nmr spectrum of 13,14-dihydro-15-keto-PGD₂ ethyl ester (11) is shown inFIG. 1.

EXAMPLE 2 (CF. SYNTHETIC CHART 1) Synthesis of13,14-dihydro-15-keto-PGD₂ (11), R=H

Carboxylic acid (8) was deketalized according to the usual method togive 13,14-dihydro-15-keto-PGF₂ α (10). The resultant (10) was oxidizedwith Jones reagent to give 13,14-dihydro-15-keto-PGD₂ (11), R=H.

EXAMPLE 3 (CF. SYNTHETIC CHART 1) Synthesis of13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me

13,14-Dihydro-15-keto-PGD₂ (11), R=H, was converted into methyl esterusing diazo-methane. After chromatography (ethyl acetate/hexane(1:3)),13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me, was obtained. Yield,0.0610 g (50%).

Carboxylic acid (8) was converted into methyl ester (9), R=Me, with DBUand methyl iodide in acetonitrile, then into 13,14-dihydro-15-keto-PGD₂methyl ester (11), R=Me.

NMR spectrum of 13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me, isshown in FIG. 2.

EXAMPLE 4 (CF. SYNTHETIC CHART 1) Synthesis of13,14-dihydro-15-keto-PGD₂ n-butyl ester (11), R=n-Bu

In the manner analogous to that described in Example 1, except thatcarboxylic acid (8) obtained from (-)-Corey lactone (1) was convertedinto n-butyl ester (9), R=n-Bu, with n-butyl bromide and DBU inacetonitrile, 13,14-dihydro-15-keto-PGD₂ n-butyl ester (11), R=n-Bu, wasobtained.

NMR spectrum of 13,14-dihydro-15-keto-PGD₂ n-butyl ester (11), R=n-Bu,is shown in FIG. 3.

EXAMPLE 5 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-20-methoxy-PGD₂ methyl ester (20), R=Me

In the same manner as in Example 1,13,14-dihydro-15-keto-20-methoxy-PGD₂ methyl ester (20) was synthesizedusing (-)-Corey lactone (1) and dimethyl(7-methoxy-2-oxoheptyl)phosphonate prepared by the conventional method.To produce methyl ester of carboxylic acid (17), diazomethane or methyliodide and DBU can be use.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-PGD₂ methyl ester (20),R=Me, is shown in FIG. 4.

EXAMPLE 6 (CF. SYNTHETIC CHART 3) Synthesis of13,14-dihydro-15-keto-20-methoxy-PGD₂ (31) (6-1) Synthesis of1S-2-oxa-3-oxo-6R-(3R,S-hydroxy-8-methoxy-1-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(21)

1S-2-Oxa-3-oxo-6R-(8-methyoxy-3-oxo-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)-octane(13) (1.584 g) was reduced with NaBH₄ in a mixed solvent (methanol/THF(3:2)) (50 ml), then chromatographed (ethyl acetate/hexane (2:1)) togive alcohol (21). Yield, 0.7070 g.

(6-2) Synthesis of1S-2-oxa-3-oxo-6R-(3R,S-hydroxy-8-methoxy-1-octyl)-7R-hydroxy-cis-bicyclo-(3,3,0)octane(22)

1S-2-Oxa-3-oxo-6R-(3R,S-hydroxy-8-methoxy-1-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo-(3,3,0)octane(21) (0.7070 g) was dissolved in a mixed solvent of methanol/THF (3:2)(50 ml), potassium carbonate (0.2034 g) was added thereto and stirredfor 4 hours. According to the conventional treatment, diol (22) wasobtained. Yield, 0.3925 g.

(6-3) Synthesis of1S-2-oxa-3-oxo-6R-(3R,S-t-butyldimethylsilyloxy-8-methoxy-1-octyl)-7R-t-butyldimethylsilyloxy-cis-bicyclo(3,3,0)octane(23)

Diol (22) (0.3925 g) was converted into the corresponding silyl ether(23) using t-butyldimethylsilyl chloride (0.5928 g) anddimethylaminopyridine (0.640 g) in dichloromethane. Yield, 0.3642 g.

(6-4) Synthesis of13,14-dihydro-11,15R,S-di(t-butyldimethylsilyloxy)-20-methoxy-PGF₂.sup.αmethyl ester (26)

Silyl ether (23) (0.3642 g) was reduced with DIBALH (1.5-M, 1.4 ml) intoluene (20 ml), and according to the conventional treatment, lactol(24) was obtained. Separately, ylide was prepared from (4-carboxybutyl)triphenylphosphonium bromide (1.223 g) and potassium butoxide (0.6194 g)in THF (180 ml), to which was added the above lactol. After the reactionwas completed, carboxylic acid (25) was obtained by the conventionaltreatment. The resultant was treated with diazomethane to give methylester (26). Yield, 0.176 g.

(6-5) Conversion of the compound (26) into tetrahydro pyranyl ether

The above methyl ester (26) (0.176 g) was converted intotetrahydropyranyl ether (27) with p-toluenesulfonic acid (catalyticamount) and dihydropyran in dichloromethane (10 ml). Yield, 0.222 g.

(6-6) Synthesis of13,14-dihydro-15R,S-hydroxy-20-methoxy-9-(2-tetrahydropyranyl)oxy-PGF.sub.2α(29)

Methyl ester (27) (0.2220 g) was dissolved in THF (10 ml), to which wasadded tetrabutylammonium fluoride (1-M, 1.91 ml), and allowed to standat room temperature. According to the conventional treatment, diol (28)was obtained. Yield, 0.816 g.

The diol (28) (0.816 g) was dissolved in methanol (10 ml), to which wasadded 20% sodium hydroxide (5 ml) and held at room temperature for 2hours. According to the conventional treatment, carboxylic acid (29) wasobtained.

(6-7) Synthesis of 13,14-dihydro-15-keto-20-methoxy-PGD₂ (31)

Carboxylic acid (29) was oxidized with Jones reagent in actone (10 ml)at -37° C. (2.6-M, 0.15 ml).13,14-Dihydro-15-keto-20-methoxy-9-(2-tetrahydropyranyl)oxy-PGD₂ (30)was obtained according to the conventional treatment. The resultingcompound (30) was dissolved in a mixed solvent (acetic acid/water/THF(4:2:1)) (7 ml) and held at 40°-43° C. for 3 hours. After theconventional treatment, the compound was chromatographed (ethylacetate/hexane (4:1)) to give 13,14-dihydro-15-keto-20-methoxy-PGD₂(31). Yield, 0.059 g.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-PGD₂ (31) is shown inFIG. 5.

EXAMPLE 7 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ methyl ester (32)##STR11##

In the same manner as in Example 5,13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ methyl ester (32) wassynthesized using (-)-Corey lactone (1) anddimethyl(7-methoxy-2-oxo-heptyl)phosphonate prepared by the knownmethod.

NMR spectrum of 13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ methylester (32) is shown in FIG. 6.

EXAMPLE 8 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-20-methoxyethyl-PGD₂ methyl ester (33) ##STR12##

In the same manner as in Example 5,13,14-dihydro-15-keto-20-methoxyethyl-PGD₂ methyl ester (33) wassynthesized using (-)-Corey lactone (1) anddimethyl(7-methoxy-2-oxononyl)phosphonate prepared by the known method.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxyethyl-PGD₂ methyl ester(33) is shown in FIG. 7.

EXAMPLE 9 (CF. SYNTHETIC CHARTS 2 AND 4) Synthesis of13,14-dihydro-15-keto-20-methoxy-Δ² -PGD₂ methyl ester (38) (9-1)Synthesis of13,14-dihydro-15,15-ethylenedioxy-20-methoxy-9,11-di(t-butyldimethylsilyloxy)-PGF₂α methyl ester (34)

13,14-Dihydro-15,15-ethylenedioxy-20-methoxy-PGF₂ α methyl ester (18)(0.5472 g) was converted into13,14-dihydro-15,15-ethylenedioxy-20-methoxy-9,11-di(t-butyldimethylsilyloxy)PGF₂α methyl ester (34) using t-butyldimethylsilyl chloride (0.9428 g) andimidazole (0.8519 g) in DMF (10 ml). Yield, 0.8015 g.

(9-2) Synthesis of13,14-dihydro-15,15-ethylenedioxy-20-methoxy-9,11-di(t-butyldimethylsilyloxy)-Δ²-PGF₂ α methyl ester (36)

Lithium cyclohexylisopropylamide was prepared fromcyclohexylisopropylamine (0.07 ml) and n-butyllithium (1.6-M, 0.265 ml)in THF (1 ml). To the resultant was added dropwise a solution of methylester (34) (0.1412 g) in THF (4 ml) and stirred for 2 hours. A solutionof diphenyl diselenide (0.132 g) and HMPA (0.074 ml) in THF (2 ml) wasadded, and the mixture was stirred at -70° C. for one hour and -40°C.--30° C. for 1.5 hours. According to the conventional treatment,selenide (35) (0.1247 g) was obtained. Selenide (35) (0.1247 g) wasdissolved in ethyl acetate (6 ml) and methanol (4 ml), and stirred atroom temperature with aqueous hydrogen peroxide (30%) (0.5 ml) for onehour. The crude product obtained by the conventional treatment waschromatographed (ethyl acetate/hexane (1:6)) to give Δ² -PGE₂ α-methylester (36). Yield, 0.091 g.

(9-3) Synthesis of 13,14-dihydro-15-keto-20-methoxy-Δ² -PGF₂ α methylester (37)

Δ² -PGF₂ α methyl ester (36) (0.5458 g) was dissolved in a mixed solvent(acetic acid/water/THF (10:3.3:1)) (20 ml) and the resulting solutionwas held at 55° C. for 3.5 hours. By the conventional treatment,13,14-dihydro-15-keto-20-methoxy-Δ² -PGF₂ α methyl ester (37) wasobtained. Yield, 0.2935 g.

(9-4) Synthesis of 13,14-dihydro-15-keto-20-methoxy-Δ² -PGD₂ methylester (38)

13,14-Dihydro-15-keto-20-methoxy-Δ² -PGF₂ α methyl ester (37) (0.3277 g)was oxidized with Jones reagent in acetone (20 ml) at -40° C. (2.67-M,0.25 ml). After the conventional treatment, the resulting crude productwas chromatographed (ethyl acetate/hexane (6:4)) to give13,14-dihydro-15-keto-20-methoxy-Δ² -PGD₂ methyl ester (38). Yield,0.204 g.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-Δ² -PGD₂ methyl ester(38) is shown in FIG. 8.

EXAMPLE 10 Synthesis of13,14-dihydro-15-keto-18-methoxy-19,20-bisnor-PGD₂ methyl ester (39)##STR13##

13,14-Dihydro-15-keto-18-methoxy-19,20-bisnor-PGD₂ methyl ester (39) wasobtained in the same manner as in Example 5 using (-)-Corey lactone (1)and dimethyl(5-methoxy-2-oxopentyl)phosphonate.

NMR spectrum of 13,14-dihydro-15-keto-18-methoxy-19,20-bisnor-PGD₂methyl ester (39) is shown in FIG. 9.

EXAMPLE 11 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-20-methoxy-PGD₂ ethyl ester (20), R=Et ##STR14##

In the same manner as in Example 5, except that13,14-dihydro-15,15-ethylenedioxy-20-methoxy-PGF₂ α(17) was convertedinto ethyl ester (18) with ethyl iodide and DBU in acetonitrile,13,14-dihydro-15-keto-20-methoxy-PGD₂ ethyl ester (20) was prepared.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-PGD₂ ethyl ester (20),R=Et, is shown in FIG. 10.

EXAMPLE 12 (CF. SYNTHETHIC CHART 2) Synthesis of13,14-dihydro-15-keto-20-methoxy-PGD₂ n-butyl ester (20), R=n-Bu

In the same manner as in Example 5, except that13,14-dihydro-15,15-ethylenedioxy-20-methoxy-PGF₂ α(17) was convertedinto n-butyl ester (18) with n-butyl iodide and DBU in acetonitrile,13,14-dihydro-15-keto-20-methoxy-PGD₂ n-butyl ester (20), R=n-Bu, wasprepared.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-PGD₂ n-butyl ester(20), R=n-Bu, is shown in FIG. 11.

EXAMPLE 13 Synthesis of13,14-dihydro-15-keto-16R,S-methyl-20-methoxy-PGD₂ methyl ester (40)##STR15##

13,14-Dihydro-15-keto-16R,S-methyl-20-methoxy-PGD₂ methyl ester (40) wasprepared in the same manner as in Example 5 using (-)-Corey lactone (1)and dimethyl(3-methyl-20-methoxy-2-oxoheptyl)phosphonate obtained by theknown method.

NMR spectrum of 13,14-dihydro-15-keto-16R,S-methyl-20-methoxy-PGD₂methyl ester (40) is shown in FIG. 12.

EXAMPLE 14 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-19-ethoxy-20-nor-PGD₂ methyl ester (41) ##STR16##

13,14-Dihydro-15-keto-19-ethoxy-20-nor-PGD₂ methyl ester (41) wasprepared in the same manner as in Example 5 using (-)-Corey lactone (1)and dimethyl(6-ethoxy-2-oxohexyl)phosphonate obtained by the knownmethod.

NMR spectrum of 13,14-dihydro-15-keto-19-ethoxy-20-nor-PGD₂ methyl ester(41) is shown in FIG. 13.

EXAMPLE 15 (CF. SYNTHETIC CHART 2) Synthesis of13,14-dihydro-15-keto-19-ethoxy-20-nor-PGD₂ n-butyl ester (42).##STR17##

13,14-Dihydro-15-keto-19-ethoxy-20-nor-PGD₂ n-butyl ester (42) wasprepared in the same manner as in Example 5 using (-)-Corey lactone (1)and dimethyl(6-ethoxy-2-oxohexyl)phosphonate obtained by the knownmethod.

NMR spectrum of 13,14-dihydro-15-keto-19-ethoxy-20-nor-PGD₂ n-butylester (42) is shown in FIG. 14.

EXAMPLE 16 (CF. SYNTHETIC CHART 5) Synthesis of (±)13,14-dihydro-15-keto-5,6-dehydro-PGD₂ methyl ester (50) (16-1)Synthesis of (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis(t-butyldimethylsilyl)oxy-PGE₂methyl ester (44).

(±) 1-Iodo-3-(2-tetrahydropyranyl)oxy-1-octene (1.852 g) was convertedinto vinyllithium with t-butyllithium (in pentane, 1.92-M, 5.8 ml) inether (25 ml) at -78° C. Separately, copper iodide (0.9522 g) wassuspended in THF (25 ml), to which was added tri-n-butylphosphine (3.24ml), and the mixture was homogenized and the temperature was brought to-78° C. The previously prepared vinyllithium solution was added to theresultant and stirred at -78° C. for 15 minutes. To the resultant wasadded dropwise a solution of (±)4-t-butyldimethylsilyloxy-2-cyclopentenone (43) (1.012 g) in THF (25ml). After adding HMPA (4.62 ml) dropwise, a solution oftriphenylstannane chloride (2.029 g) in THF (10 ml) was added. Afterstirring at -78° C. for 30 minutes, the temperature was allowed to riseto -35° C. A solution of 1-iodo-6-carbomethoxy-2-hexyne (5.321 g) inHMPA (4.62 ml) was added dropwise to the mixture, and the resultant wasstirred at -40° C. --30° C. for 35 hours, then let to stand at -20° C.for 11.5 hours. The crude product obtained after the conventionaltreatment was chromatographed (ethyl acetate/hexane (1:5)) to give (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGE₂methyl ester (44) (1.510 g).

(16-2) Synthesis of (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF₂ αmethyl ester (45).

(±)13,14-Dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGE₂methyl ester (44) (1.510 g) was reduced with sodium borohydride (NaBH₄)at -12° C. in ethanol to give (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF₂ αmethyl ester (45). Yield, 0.9842 g.

In this case, 9β-isomer (46) (0.2385 g) was obtained as a by-product.

(16-3) Synthesis of (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrahydropyranyl)oxy-PGF₂α methyl ester (47).

(±)13,14-Dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF₂ αmethyl ester (45) (0.9842 g) was converted into (±)13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetranydropyranyl)oxy-PGF₂α methyl ester (47) with dihydropyran and p-toluenesulfonic acid indichloromethane (20 ml). Yield, 0.7580 g.

(16-4) Synthesis of (±)13,14-dihydro-5,6-dehydro-11,15R,S-dihydroxy-9-(tetrahydropyranyl)oxy-PGF.sub.2α methyl ester (48).

(±)13,14-Dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrahydropyranyl)-oxy-PGF₂α methyl ester (47) (0.4484 g) was converted to diol (48) usingtetrabutylammonium fluoride (1-M, 1.3 ml) in THF (50 ml). Yield, 0.2174g.

(16-5) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-9-(2-tetrahydropyranyl)oxy-PGD₂ methylester (49).

Diol (48) (0.2174 g) was oxidized with Jones reagent (2.67M, 0.05 ml) inacetone (10 ml) to give13,14-dihydro-15-keto-5,6-dehydro-9-(2-tetrahydropyranyl)oxy-PGD₂ methylester (49). Yield, 0.103 g.

(16-6) Synthesis of 13,14-dihydro-15-keto-5,6-dehydro-PGD₂ methyl ester(50).

13,14-Dihydro-15-keto-5,6-dehydro-9-(2-tetrahydropyranyl)oxy-PGD₂ methylester (49) (0.103 g) was dissolved in a mixed solvent (aceticacid/THF/water (3:1:1)) (50 ml) and held at room temperature overnight.After the conventional treatment, the crude product was chromatographedto give (±) 13,14-dihydro-15-keto-5,6-dehydro-PGD₂ methyl ester (50).Yield, 0.0498 g.

NMR spectrum of (±)-13,14-dihydro-15-keto-5,6-dehydro-PGD₂ methyl ester(50) is shown in FIG. 16.

EXAMPLE 17 (CF. SYNTHETIC CHARTS 5 and 6) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-PGD₂ n-butyl ester (52). ##STR18##(17-1) Synthesis of13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrahydropyranyl)oxy-PGF₂α (51).

13,14-Dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrahydropyranyl)oxy-PGF₂α methyl ester (47) (0.7580 g) prepared in the same manner as in Example16 using 4R-t-butyl-dimethylsilyloxy-2-cyclopentenone (43) was convertedinto carboxylic acid (51) using 20% aqueous solution of sodium hydroxidein methanol. Yield, 0.6202 g.

(17-2) Synthesis of13,14-dihydro-5,6-dehydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-9-(2-tetrahydropyranyl)oxy-PGF₂α n-butyl ester (52).

Carboxylic acid (51) (0.1660 g) was converted into n-butyl ester (52)using DBU and n-butyl iodide (0.0916 g) in acetonitrile. Yield, 0.1648g.

The operations of Example 16 were repeated hereafter to give13,14-dihydro-15-keto-5,6-dehydro-PGD₂ n-butyl ester (52).

NMR spectrum of 13,14-dihydro-15-keto-5,6-dehydro-PGD₂ n-butyl ester(52) is shown in FIG. 15.

EXAMPLE 18 (CF. SYNTHETIC CHARTS 5 and 7) (18-1) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ methyl ester (59).

13,14-Dihydro-5,6-dehydro-11,15R,S-bis-t-butyldimethylsilyloxy-PGE₂ (44)obtained in the same manner as in Example 16 using4R-t-butyl-dimethylsilyloxy-2-cyclopentenone (43) was reduced with NaBH₄to give 13,14-dihydro-5,6-dehydro-11,15R,S-bis-t-butyldimethylsilyl-PGF₂β methyl ester (46) (0.2490 g), which was converted intotetrahydropyranyl ether (53) by the conventional method usingdihydropyran. Yield, 0.2777 g.

(18-2) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-11,15R,S-dihydro-9β-(2-tetrahydropyranyl)oxy-PGF₂β methyl ester (54).

The above tetrahydropyranyl ether (53) (0.2777 g) was converted into13,14-dihydro-15-keto-5,6-dehydro-11,15R,S-dihydro-9β-(2-tetrahydropyranyl)oxy-PGF₂β methyl ester (54) with tetrabutylammonium fluoride (1-M, 6.1 ml) inTHF solution (2 ml) at room temperature. Yield, 0.1734 g.

(18-3) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-9β-(2-tetrahydropyranyl)oxy-PGD.sub.2methyl ester (58).

The above diol (54) (0.0816 g) was oxidized with Jones reagent (2.67-M,0.17 ml) in acetone (15 ml) at -30° C. to give13,14-dihydro-15-keto-5,6-dehydro-9β-(2-tetrahydropyranyl)oxy-PGD.sub.2methyl ester (58). Yield, 0.0505 g.

(18-4) Synthesis of 13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ methylester (59).

13,14-Dihydro-15-keto-5,6-dehydro-9β-(2-tetrahydropyranyl)oxy-PGD.sub.2methyl ester (58) (0.0505 g) was dissolved in a mixed solvent (aceticacid/THF/water (3:3:1)) (6 ml) and allowed to stand at room temperaturefor 20 hours. After the conventional treatment, the resulting crudeproduct was chromatographed (hexane/ethyl acetate (3:1 -1:1)) to give13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ methyl ester (59). Yield,0.0314 g.

NMR spectrum of 13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ methyl ester(59) is shown in FIG. 17.

EXAMPLE 19 (CF. SYNTHETIC CHART 7) Synthesis of13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ (57). (19-1) Synthesis of13,14-dihydro-5,6-dehydro-15R,S-hydroxy-9β-(2-tetrahydropyranyl)oxy-PGF₂β (55).

20% Aqueous sodium hydroxide was added to13,14-dihydro-5,6-dehydro-15R,S-hydroxy-9β-(2-tetrahydropyranyl)oxy-PGF₂β methylester (54) (0.0893 g) in methanol (4 ml), and the mixture wasstirred at room temperature for 2.5 hours. After the conventionaltreatment, carboxylic acid (55) was obtained. Yield, 0.0787 g.

(19-2) Synthesis of 13,14-dihydro-15-keto-5,6-dehydro-9β-(2-tetrahydropyranyl)oxy-PGD₂ (56).

The above diol (55) (0.0787 g) was oxidized with Jones reagent (2.67-M,0.17 ml) in acetone (2 ml) at -40° C. After the conventional treatment,the resulting crude product was chromatographed to give13,14-dihydro-15-keto-5,6-dehydro-9β-(2-tetrahydropyranyl)oxy-PGD.sub.2(56). Yield, 0.0344 g.

(19-3) Synthesis of 13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ (57).

The above carboxylic acid (56) (0.0344 g) was dissolved in a mixedsolvent (acetic acid/THF/water (3:1:1)) (5 ml), and the solution wasstirred at room temperature for 21.5 hours. After the conventionaltreatment, the resulting crude product was chromatographed to give13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ (57). Yield, 0.0152 g.

NMR spectrum of 13,14-dihydro-15-keto-5,6-dehydro-9β-PGD₂ (57) is shownin FIG. 18.

EXAMPLE 20 Synthesis of 13,14-dihydro-15-keto-16,16-dimethyl-PGD₂ methylester (60). ##STR19##

In the same manner as in Example 1 using (-)-Corey lactone (1) anddimethyl(3,3-dimethyl-2-oxoheptyl) phosphonate prepared by the knownmethod, 13,14-dihydro-15-keto-16,16-dimethyl-PGD₂ methyl ester (60) wasprepared.

NMR spectrum of 13,14-dihydro-15-keto-16,16-dimethyl-PGD₂ methyl ester(60) is shown in FIG. 19.

EXAMPLE 21 (CF. SYNTHETIC CHART 1) Synthesis of (±)13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me.

In the same manner as in Example 1 using (±)-Corey lactone, (±)13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me, was prepared.

NMR spectrum of 13,14-dihydro-15-keto-PGD₂ methyl ester (11), R=Me, isshown in FIG. 20.

EXAMPLE 22 Synthesis of 13,14-dihydro-15-keto-19-methyl-PGD₂ methylester (61). ##STR20##

In the same manner as in Example 1 using (-)-Corey lactone (1) anddimethyl(6-methyl-2-oxo-heptyl)phosphonate,13,14-dihydro-15-keto-19-methyl-PGD₂ methyl ester (61) was prepared.

NMR spectrum of 13,14-dihydro-15-keto-19-methyl-PGD₂ methyl ester (61)is shown in FIG. 21.

EXAMPLE 23 Synthesis of13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD₂ methyl ester (62)##STR21##

In the same manner as in Examples 1 and 22 using (-)-Corey lactone anddimethyl(3,3-dimethyl-7-methoxy-2-oxoheptyl)phosphonate,13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD₂ methyl ester (62)was prepared.

NMR spectrum of 13,14-dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD₂methyl ester (62) is shown in FIG. 22.

EXAMPLE 24 (CF. SYNTHETIC CHART 8) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-PGD₂ methyl ester (74) (24-1)Synthesis of1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3,S-hydroxy-1-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(64)

1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-oxo-1-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(63) (2.77 g), which was prepared in the same manner as in Example 1using (-)-Corey lactone (1) anddimethyl(3R,S-fluoro-2-oxoheptyl)phosphonate, was reduced with NaBH₄ inmethanol (90 ml) at 0° C. to give alcohol (64). Yield, 2.91 g.

(24-2) Synthesis of1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-hydroxy-1-octyl)-7R-hydroxy-cis-bicyclo-(3,3,0)-octane(65)

The above alcohol (64) (2.91 g) was converted into diol (65) usingpotassium carbonate (0.82 g) in methanol (120 ml). Yield, 1.61 g.

(24-3) Synthesis of3R-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-t-butyldimethylsilyloxy-1-octyl)-7R-(t-butyldimethylsilyl)oxy-cis-bicyclo(3,3,0)-octane(66)

The above diol (65) (1.61 g) was converted into bis-silylether (66)using t-butyl-dimethylchlorosilane and imidazole in DMF (3 ml). Yield,2.47 g.

(24-4) Synthesis of16R,S-fluoro-13,14-dihydro-11,15R,S-bis(t-butyldimethylsilyloxy)-PGF₂ α(68)

Bis-silyl ether (66) (2.47 g) was reduced with DIBAL-H according to theconventional method to give lactol (67). Ylide obtained from(4-carboxybutyl)-triphenylphosphonium bromide (6.33 g), sodium hydride(60%, 1.20 g) in DMSO (160 ml), was stirred with lactol (67) in DMSO (60ml) at room temperature for 15 hours. After the conventional treatment,0.887 g of 11,15R,S-bis-t-butyldimethylsilyloxy-PGF₂ α(68) and 0.996 gof 9,15-bis-t-butyldimethylsilyloxy-PGF₂ α(69) were obtained.

(24-5) Synthesis of16R,S-fluoro-13,14-dihydro-11,15R,S-bis-(t-butyldimethylsilyl)oxy-PGF.sub.2αmethyl ester (70)

To 11,15R,S-bis-t-butyldimethylsilyloxy-PGF₂ α (68) (0.887 g) were addedDBU (0.46 ml) and methane iodide (0.47 ml) in acetonitrile (25 ml), andthe mixture was held at 40° C. for 3.5 hours. According to theconventional treatment, methyl ester (70) was obtained. Yield, 0.738 g.

(24-6) Synthesis of tetrahydropyranyl ether (71)

The above methyl ester (70) was converted into tetrahydropyranyl ether(71) using dihydropyran and p-toluenesulfonic acid.

(24-7) Synthesis of16R,S-fluoro-13,14-dihydro-15R,S-hydroxy-9-(2-tetrahydropyranyl)oxy-PGF.sub.2α methyl ester (72)

The above pyranyl ether (71) was dissolved in THF (20 ml), to which wasadded a solution of tetrabutylammonium fluoride in THF (1.0-M, 18 ml).The resulting solution was stirred at room temperature for 2 hours. Thecrude product obtained by the conventional treatment was chromatographed(hexane/ethyl acetate (2:1-1:1)) to give16R,S-fluoro-13,14-dihydro-15R,S-hydroxy-9-(2-tetrahydropyranyl)oxy-PGF.sub.2α methyl ester (72). Yield, 0.487 g.

(24-8) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-9-(2-tetrahydropyranyl)oxy-PGD₂methyl ester (73)

The above diol (72) (0.487 g) was oxidized with Jones reagent (2.67-M,1.19 ml) in acetone (45 ml) at -20° C. After the conventional treatment,the resulting crude product was chromatographed (hexane/ethyl acetate(5:1)) to give13,14-dihydro-15-keto-16R,S-fluoro-9-(2-tetrahydropyranyl)oxy-PGD₂methyl ester (73). Yield, 0.373 g.

(24-9) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-PGD₂ methyl ester(74)

The above tetrahydropyranyl ether (73) (0.373 g) was dissolved in amixed solvent (acetic acid/THF/water (3:1:1)) (25 ml) and held at 45° C.for 7 hours. After the conventional treatment, the resulting crudeproduct was chromatographed (hexane/ethyl acetate (4:1)) to give13,14-dihydro-15-keto-16R,S-fluoro-PGD₂ methyl ester (74). Yield, 0.221g.

The NMR data of 13,14-dihydro-15-keto-16R,S-fluoro-PGD₂ -methyl ester(74) is as follow: σ:0.91(3H, t, J=6 Hz), 1,1-2.93(23H, m), 2.64(3H, s),4.3-4.5(1.5H, m), 4.98(0.5H, dd, J=6 Hz), 5.50(2H, m).

EXPERIMENT 1 Sleep-Inducing Action by the Administration of13,14-dihydro-15-keto-PGDs into Cerebral Third Ventricle

As test samples PGD₂ was purchased from Funakoshi Yakuhin K. K. and13,14-dihydro-15-keto-PGD₂ was obtained from the above Examples.

Male rats of SD strain (weight: 350-400 g) were used as test animals.

The electroencephalogram was bipolarly recorded with screw electrodesfixed to the frontal part of the skull chronically. The electrodes forrecording electromyogram were inserted into musculus tibialis posteriorand fixed.

A cannula (diameter: 0.35 mm) of stainless steel was inserted into thecerebral third ventricle for administration of the test samples.

The experiments were made after elapse of at least one week ofconvalescence of rats after operation under the condition that the ratscould freely move in cages of 25 cm (D)×25 cm (W)×45 cm (H).

Each test sample was dissolved in sterilized phisiological saline. Theobtained each solution was injected into the cerebral third ventricle ofthe test animals separately at a rate of 20 μl/hour during 10 hours from20:00-6:00 o'clock. As a control group, rats were administeredphysiological saline one day before the administration of the testsamples.

The amount of sleep of rats was determined from the electroencephalogramand electromyogram recorded on the polygraph over 24 hours. Slow wavesleeping amount was determined using the slow wave with high amplitudeas an indicator.

The result from the administration of 13,14-dihydro-15-keto-PGD₂ isshown in FIG. 23, in which (a) shows the results from13,14-dihydro-15-keto-PGD₂ and (b) shows the results from theadministration of the physiological saline.

FIG. 23 indicates that the amount of the sleep increased by theadministration of 13,14-dihydro-15-keto-PGD₂ into cerebral ventricles.

The results are also shown in Table 1.

EXPERIMENT 2 Sleep-Inducing Action Caused through PeripheralAdministration (Oral, Intravenous and Subcutaneous Administration) of13, 14-dihydro-15-keto-PGDs

As test samples 13,14-dihydro-15-keto-PGDs obtained in above Examplesand PGD₂ (available from Funakoshi Yakuhin K. K.) as control referencewere used. Five weeks aged, male mice of the Slc-ddy strain wereemployed as test animals. The electroencephalogram was bipolarlyrecorded with electrodes fixed to the frontal part of the skull.Electromyogram was recorded with electrodes fixed in the musculustibialis posterior.

Mice were used after elapse of at least one week of convalencence. Eachtest animal was placed on a triangular platform (10 cm×10 cm×10 cm)being set 30 cm high from the floor, with their levels of wakefulnessbeing maintained in the excited state.

Oral administration was conducted by dissolving test sample inphysiological saline containing 0.5% of carboxymethylcellulose in theratio of 10 ml/kg. Intravenous administration was carried out by givinga solution of a test sample in physiological saline through a tail vein.Each group of test animals employed consisted of three to five mice.

A test sample was administered to mice 20 minutes after having beenplaced on the platform, and the polygraphic recordings ofelectroencephalograms and electromyograms were carried out over the 80minutes period thereafter.

On the bases of the recordings obtained, the levels of wakefulnessand/or sleep are classified into the following four categories. Thus,(i) the aroused wave stage (AW) where the electroencephalogram exhibitslow amplitude and high frequency waves mostly ranging from 7 to 8 HZ,while the clear-appearance of electromyogram is revealed; (ii) the slowwave light sleep stage (SWLS) where the electroencephalogram is observedto produce a change toward higher-amplitude slower waves (not greaterthan 4 HZ), but for the duration of not longer than 30 seconds; (iii)the slow wave deep sleep stage (SWDS) where the electroencephalogramcauses a change toward higher-amplitude slower waves with its durationbeing greater than 30 seconds; and (iv) the paradoxical sleep stage (PS)where the electroencephalogram constitutes low-amplitude fast wave, withthe entirely disappeared electromyographic signal. In FIGS. 24 to 27,the arrow mark denotes a point of time when test sample was given.

FIG. 24 shows the result of sleep-elapse change when the physiologicalsaline was intravenously administered, and FIG. 25 shows the result whenthe methyl ester of 13,14-dihydro-15-keto-PGD₂ (5 mg/kg) wasintravenously administered. As apparent from FIG. 24 the administrationof physiological saline did not cause SWDS, whereas the methyl ester of13,14-dihydro-15-keto-PGD₂ (5 mg/kg administration) induced sleep withSWDS. Similar thereto 5 mg/kg administration of ethyl ester of13,14-dihydro-15-keto-PGD₂ and n-butyl ester of13,14-dihydro-15-keto-PGD₂ induced sleep with SWDS respectively.

FIG. 26 shows the result of sleep-elapse change when a physiologicalsaline containing 0.5% of carboxymethylcellulose was orallyadministered, and FIG. 27 shows the result when 5 mg/kg of methyl esterof 13,14-dihydro-15-keto-20-methoxy-PGD₂ was orally administered. Asapparent from the both figures the former did not induce SWDS whereasthe latter induce sleep with SWDS. Similar to the above the oraladministration of methyl ester of13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ and methyl ester of13,14-dihydro-18-methoxy-18,19-dinor-PGD₂ (5 mg/kg) induced sleep withSWDS.

The oral administration of ethyl ester of13,14-dihydro-15-keto-20-methoxy-PGD₂ induced sleep with SWDS in 10mg/kg. Other test samples, 13,14-dihydro-15-keto-PGDs, showed sleepinducing action with SWDS through oral administration of 10 mg/kg.

The results of the above experiment as to the sleep inducing action areshown in Table 1, wherein "+" exhibits the presence of sleep inducingaction with SWDS and "-" exhibits the absence of sleep inducing actionwith SWDS.

EXPERIMENT 3 Sedation by 13,14-dihydro-15-keto-PGDs throughAdministration of Cisterna Magma

As test samples there were used 13,14-dihydro-15-keto-PGD₂, methyl esterof 13,14-dihydro-15-keto-PGD₂, ethyl ester of13,14-dihydro-15-keto-PGD₂, and n-butyl ester of13,14-dihydro-15-keto-PGD₂ as embodiments of the present invention, andPGD₂ (available from Funakoshi Yakuhin K. K.) and physiological salineas comparative experiments.

Each test sample (1 mg) was dissolved in ethyl alcohol (1 ml) to prepareeach solution, a given amount of which was taken into test tubesrespectively. The solution was dried under nitrogen stream, to whichsterile physiological saline was added and then subjected to ultrasonicwave to form micells. Ten μl of each solution of the test sample wasadministered into cisterna magma, and as a comparative experiment 10 μlof physiological saline was administered.

As test animals 4 to 6 male mice of ddY strain (weight: 32-34 g) wereemployed.

The amount of movement of test mice was determined by Automex II(available from Colombus Instruments Co.). The amount was expressed by"counts". The less counts indicates the higher action of sedativeactivity.

13,14-dihydro-15-keto-PGD₂, methyl ester 13,14-dihydro-15-keto-PGD₂,ethyl ester of 13,14-dihydro-15-keto-PGD₂, and n-butyl ester of13,14-dihydro-15-keto-PGD₂ exhibited sedation at 0.2 mg/kg and PGD₂ didat 0.02 mg/kg. The results are shown in Table 1.

EXPERIMENT 4 Sedative Activity Caused through Peripheral Administration(Oral, Intravenous and Subcutaneous Administration) of13,14-dihydro-15-keto-PGDs

As test and control reference samples, there were used the samecompounds as in Experiment 2.

Each group of test animals used consisted of 6 to 14 five-week aged,male mice of the Slc-ddY strain.

In order to measure the amounts of activities of mice, MK-Animex (AnimexActivity Meter, Model KSE: available from Muromachi Kikai K. K.) wasemployed to take measurements of the amounts of activities as a count,whereby the decrease in the amounts of activities indicated the presenceof sedative activity.

The above-described test samples were given to mice and evaluated forthe development of sedative activity, with the evaluation results shownin Table 1.

PGD₂ exhibited sedative activity by the intravenous administration of 1mg/kg, but 13,14-dihydro-15-keto-PGD₂ did not exhibited the sameactivity even by the administration of 5 mg/kg. Methyl ester, ethylester and n-butyl ester of 13,14-dihydro-15-keto-PGD₂ exhibited thesedative activity by the intravenous administration of 5 mg/kgrespectively.

Methyl ester of 13,14-dihydro-15-keto-20-methoxy-PGD₂ exhibited sedativeactivity by oral administration of 5 mg/kg as well as intravenousadministration of 1 mg/kg. Methyl ester of13,14-dihydro-15-keto-3R,S-methyl-20-methoxy-PGD₂ exhibited sedativeactivity by the oral administration of 5 mg/kg. The other test sampleexhibited sedative activity by the intravenous administration of 10mg/kg.

                  TABLE 1                                                         ______________________________________                                                                 Sedative Effect                                                               (Inhibition of                                       Sample Induction of Sleep                                                                              Ultromotivity)                                       ______________________________________                                         1     i.C.V.  *.sup.1 600                                                                          fmol/min +                                                                             i.Cist                                                                              *.sup.2 0.2                                                                        mg/kg +                                                            I.V.  5    mg/kg -                              2                             i.Cist                                                                              0.2  mg/kg +                                    I.V.    5      mg/kg +  I.V.  5    mg/kg +                              3                             i.Cist                                                                              0.2  mg/kg +                                    I.V.    5      mg/kg +  I.V.  5    mg/kg +                              4                             i.Cist                                                                              0.2  mg/kg +                                    I.V.    5      mg/kg +  I.V.  5    mg/kg +                              5     P.O.*.sup.3                                                                           5      mg/kg +  P.O.  5    mg/kg +                                            3      mg/kg ±                                                             1      mg/kg -  I.V.  1    mg/kg +                                    I.V.*.sup.4                                                                           5      mg/kg +        5    mg/kg +                              6     P.O.    5      mg/kg +  P.O.  5    mg/kg +                                            3      mg/kg -                                                  7     P.O.    10     mg/kg +  I.V.  10   mg/kg +                                            5      mg/kg +                                                                3      mg/kg -                                                   8    P.O.    10     mg/kg +  I.V.  10   mg/kg +                                            5      mg/kg ±                                                             3      mg/kg -                                                  9     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             10     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             11     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             12     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             13     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             14     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             15     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             16     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             17     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             18     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             19     P.O.    10     mg/kg +  I.V.  10   mg/kg +                             Ref. Ex.                                                                      20     i.C.V.  600    fmol/min +                                                                             i.Cist                                                                              0.02 mg/kg +                                    P.O.    5      mg/kg -  P.O.  10   mg/kg -                                    I.V.    1      mg/kg -  I.V.  1    mg/kg +                                    S.C.*.sup.5                                                                           0.5    mg/kg -  S.C.  0.5  mg/kg +                             21     P.O.    10     ml/kg -  P.O.  20   ml/kg -                                    I.V.    10     ml/kg -  I.V.  10   ml/kg -                                                            S.C.  10   mg/kg -                             ______________________________________                                         Samples:                                                                      1: 13,14dihydro-15-keto-PGD.sub.2                                             2: 13,14dihydro-15-keto-PGD.sub.2 methyl ester                                3: 13,14dihydro-15-keto-PGD.sub.2 ethyl ester                                 4: 13,14dihydro-15-keto-PGD.sub.2 nbutyl ester                                5: 13,14dihydro-15-keto-20-methoxy-PGD.sub.2 methyl ester                     6: 13,14dihydro-15-keto-3R,S-methyl-20-methoxy-PGD.sub.2 methyl ester         7: 13,14dihydro-15-keto-18-methoxy-19,20-bisnor-PGD.sub.2 methyl ester        8: 13,14dihydro-15-keto-20-methoxy-PGD.sub.2 ethyl ester                      9: 13,14dihydro-15-keto-20-methoxy-PGD.sub.2 nbutyl ester                     10: 13,14dihydro-15-keto-20-methoxy-PGD.sub.2                                 11: 13,14dihydro-15-keto-20-methoxy-Δ.sup.2PGD.sub.2 methyl ester       12: 13,14dihydro-15-keto-16R,S-methyl-20-methoxy-PGD.sub.2 methyl ester       13: 13,14dihydro-15-keto-20-methoxyethyl-PGD.sub.2 methyl ester               14: 13,14dihydro-15-keto-19-ethoxy-20-nor-PGD.sub.2 methyl ester              15: 13,14dihydro-15-keto-19-ethoxy-20-nor-PGD.sub.2 nbutyl ester              16: 13,14dihydro-15-keto-16,16-dimethyl-20-methoxy-PGD.sub.2 methyl ester     17: 13,14dihydro-15-keto-19-methyl-PGD.sub.2 methyl ester                     18: 13,14dihydro-15-keto-16R,S-fluoro-PGD.sub.2 methyl ester                  19: 13,14dihydro-15-keto-5,6-dehydro-9R-PGD.sub.2 methyl ester                Ref. Ex. 20: PGD.sub.2 (manufactured by Funakoshi Yakuhin K.K.)               21: Physiological saline                                                      *.sup.1 intraventricular administration                                       *.sup.2 intrapostcisternal administration                                     *.sup.3 oral administration                                                   *.sup.4 intravenous injection                                                 *.sup.5 subcutaneous injection                                                ##STR22##

What is claimed is:
 1. A prostaglandin D represented by formula(I):wherein (X) is ##STR23## R₁ is hydrogen, a physiologicallyacceptable salt residue or a physiologically acceptable alkyl esterresidue; R₂ is hydrogen or methyl; R₃ is hydroxyl, methyl orhydroxymethyl; R₄ and R₅, which may be the same or different, eachrepresents hydrogen, methyl or halogen; when at least 1 of R₄ and R₅ ishalogen, R₆ is C₁₋₉ alkyl which may be branched or contain a double bondor is a C₁₋₉ alkyl containing a C₁₋₂ alkoxy substituent; or when R₄ andR₅ are independently hydrogen or methyl, R₆ is C₆₋₉ alkyl which may bebranched or contain a double bond or a C₁₋₉ alkyl containing a C₁₋₂alkoxy substituent; and wherein carbons at the 2-3 positions may havedouble bond.
 2. A prostaglandin D of claim 1, in which R₆ is a C₄ -C₉alkyl group.
 3. A prostaglandin D of claim 1, in which R₆ is a C₂ -C₆alkyl group having a methoxy or ethoxy substituent.
 4. A prostaglandin Dof claim 1, in which R₁ is a C₁ -C₄ alkyl group.
 5. A prostaglandin D ofclaim 1, in which R₄ and/or R₅ is methyl or fluorine atom.
 6. Aprostaglandin D of claim 1, in which the R₁ ester residue is selectedfrom the group consisting of a C₁₋₄ alkyl group, an alkylsilicon groupand a tetrahydroxypyran group.
 7. A prostaglandin D of claim 1, in whichat least one of R₄ and R₅ is a halogen atom.
 8. A prostaglandin D ofclaim 7, in which the halogen atom is a fluorine atom.
 9. Aprostaglandin D of claim 8, in which both R₄ and R₅ are fluorine atoms.10. A prostaglandin D of claim 8, in which one of R₄ and R₅ is afluorine atom and the other is a hydrogen atom.
 11. A prostaglandin D ofclaim 1, in which at least one of R₄ and R₅ is a methyl group.
 12. Aprostaglandin D of claim 11, in which both R₄ and R₅ are a methyl.
 13. Aprostaglandin D of claim 11, in which one of R₄ and R₅ is a methyl groupand the other is a hydrogen atom.
 14. A prostaglandin D of claim 1, inwhich R₆ is --(CH₂)₄ --C₁₋₅ alkyl.
 15. A prostaglandin D of claim 1, inwhich R₆ is a C₆ alkyl group.
 16. A tranquilizer or soporific containingan amount effective as a tranquilizer or soporific of a prostaglandin Dof claim 1 as an active ingredient, and a pharmaceutically acceptablecarrier.
 17. A tranquilizer or soporific containing an amount effectiveas a tranquilizer or soporific of a prostaglandin D of claim 2 as anactive ingredient, and a pharmaceutically acceptable carrier.
 18. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 3 as an activeingredient, and a pharmaceutically acceptable carrier.
 19. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 4 as an activeingredient, and a pharmaceutically acceptable carrier.
 20. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 5 as an activeingredient, and a pharmaceutically acceptable carrier.
 21. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 6 as an activeingredient, and a pharmaceutically acceptable carrier.
 22. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 7 as an activeingredient, and a pharmaceutically acceptable carrier.
 23. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 8 as an activeingredient, and a pharmaceutically acceptable carrier.
 24. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 9 as an activeingredient, and a pharmaceutically acceptable carrier.
 25. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 10 as an activeingredient, and a pharmaceutically acceptable carrier.
 26. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 11 as an activeingredient, and a pharmaceutically acceptable carrier.
 27. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 12 as an activeingredient, and a pharmaceutically acceptable carrier.
 28. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 13 as an activeingredient, and a pharmaceutically acceptable carrier.
 29. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 14 as an activeingredient, and a pharmaceutically acceptable carrier.
 30. Atranquilizer or soporific containing an amount effective as atranquilizer or soporific of a prostaglandin D of claim 15 as an activeingredient, and a pharmaceutically acceptable carrier.
 31. A process fortreating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 1. 32. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 2. 33. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 3. 34. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 4. 35. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 5. 36. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 6. 37. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 7. 38. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 8. 39. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 9. 40. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 10. 41. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 11. 42. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 12. 43. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 13. 44. A process for treating a patient in need of atranquilizer which comprises administering to said patient atranquilizing effective amount of a compound of claim
 14. 45. A processfor treating a patient in need of a tranquilizer which comprisesadministering to said patient a tranquilizing effective amount of acompound of claim
 15. 46. A process for treating a patient in need of asoporific which comprises administering to said patient a soporificeffective amount of a compound of claim
 1. 47. A process for treating apatient in need of a soporific which comprises administering to saidpatient a soporific effective amount of a compound of claim
 2. 48. Aprocess for treating a patient in need of a soporific which comprisesadministering to said patient a soporific effective amount of a compoundof claim
 3. 49. A process for treating a patient in need of a soporificwhich comprises administering to said patient a soporific effectiveamount of a compound of claim
 4. 50. A process for treating a patient inneed of a soporific which comprises administering to said patient asoporific effective amount of a compound of claim
 5. 51. A process fortreating a patient in need of a soporific which comprises administeringto said patient a soporific effective amount of a compound of claim 6.52. A process for treating a patient in need of a soporific whichcomprises administering to said patient a soporific effective amount ofa compound of claim
 7. 53. A process for treating a patient in need of asoporific which comprises administering to said patient a soporificeffective amount of a compound of claim
 8. 54. A process for treating apatient in need of a soporific which comprises administering to saidpatient a soporific effective amount of a compound of claim
 9. 55. Aprocess for treating a patient in need of a soporific which comprisesadministering to said patient a soporific effective amount of a compoundof claim
 10. 56. A process for treating a patient in need of a soporificwhich comprises administering to said patient a soporific effectiveamount of a compound of claim
 11. 57. A process for treating a patientin need of a soporific which comprises administering to said patient asoporific effective amount of a compound of claim
 12. 58. A process fortreating a patient in need of a soporific which comprises administeringto said patient a soporific effective amount of a compound of claim 13.59. A process for treating a patient in need of a soporific whichcomprises administering to said patient a soporific effective amount ofa compound of claim
 14. 60. A process for treating a patient in need ofa soporific which comprises administering to said patient a soporificeffective amount of a compound of claim 15.